IFNL3 Polymorphisms Research Articles

Detect the IFNL4 Polymorphism (rs12979860) and level of IFNL4 in serum of Hepatitis C Virus in Iraqi Province

Detect the IFNL4 Polymorphism (rs12979860) and level of IFNL4 in serum of Hepatitis C Virus in Iraqi Province

FURIN, IFNL4, and TLR2 gene polymorphisms in relation to COVID-19 severity: a case-control study in Egyptian patients.

A wide range of clinical manifestations and outcomes, including liver injury, have been reported in COVID-19 patients. We investigated the association of three substantial gene polymorphisms (FURIN, IFNL4, and TLR2) with COVID-19 disease susceptibility and severity to help predict prognosis. 150 adult COVID-19-assured cases were categorized as follows: 78 patients with a non-severe presentation, 39 patients with severe disease, and 33 critically ill patients. In addition, 74 healthy controls were included. Clinical and laboratory evaluations were carried out, including complete and differential blood counts, D-dimer, lactate dehydrogenase (LDH), C-reactive protein (CRP), procalcitonin, ferritin, interleukin-6 (Il-6), and liver and kidney functions. FURIN (rs6226), IFNL4 (rs12979860), and TLR2 (rs3804099) genotyping allelic discrimination assays were conducted using real-time PCR. The FURIN, IFNL4, and TLR2 genotypes and their alleles differed significantly between COVID-19 patients and controls, as well as between patients with severe or critical illness and those with a non-severe presentation. According to a multivariable regression analysis, FURIN (C/T + T/T) and TLR2 (T/C + C/C) mutants were associated with COVID-19 susceptibility, with odds ratios of 3.293 and 2.839, respectively. FURIN C/C and IFNL4 T/T mutants were significantly linked to severe and critical illnesses. Multivariate regression analysis showed that FURIN (G/C + C/C) genotypes and IFNL4 T/T homozygosity were independent risk factors associated with increased mortality. FURIN, IFNL4, and TLR2 gene variants are associated with the risk of COVID-19 occurrence as well as increased severity and poor outcomes in Egyptian patients.

Impact of IFNL-3 (IL-28B) polymorphism on the kinetics of HBV DNA and qHBsAg and HBsAg clearance during therapy with peginterferon α-2a in patients with HBeAg-negative chronic hepatitis B, genotype D

Abstract.In recent years baseline predictors of Peg-INF response have been identified, one of the host factors may be include: genetic polymorphism IFNL-3 (IL-28B). The aim of the study. In recent years baseline predictors of Peg-INF response have been identi We investigated the effect of IFNL-3 polymorphism (SNP 12979860, SNP rs8099917) fied, one of the host on HBV DNA kinetics, qHBsAg, SVR rate and HBsAg clearance. as one of the positive prognostic factors of SBB induction. Methods. We investigated the effect of IFNL-3 polymorphism (SNP 12979860, SNP rs8099917) on the kinetics of HBV DNA, qHBsAg, the rate of SVR and HBsAg clearance. 108 patients with HBeAg-negative hepatitis B, genotype D were enrolled into the study. Results. Of 46 patients with CC SNP 12979860, a decline in the concentration of HBsAg>0.5 log10 at 12 weeks of treatment, was noticed in 23 (50.0%) persons in the group of 61 patients, and in 14 (23.0%) with CT alleles (OR=3.36, 95% CI 1.35–8.4, P<0.005). SVR was achieved in 19 (41, 3%) and 12 (19.7%), respectively (OR=3.35, 95% CI 1.12–7.5, P<0.005). Decline in HBV DNA >2 log10 at week 12 was observed in 42 (91.3%), and in 61 patients with CT — in 54 (88.5%) (OR=1.36,CI 0.32–6.75, P=0,0639). At 24 weeks of therapy, the decline in HBV DNA by 2 log10 in the group of patients with CC was detected in 46 (100%) and in those with CT in 61 patients (100%). SVR was achieved in 20 persons (43.5%) and in 11 (18%), respectively (OR=3.5, 95% CI 1.34–9.31, P<0.005). In 1 patient with TT alleles, a 2 log10 decrease in HBV DNA was recorded at 12 and 24 weeks of therapy. In the group of TT SNP rs8099917 alleles carriers (n=63), a decline in HBsAg concentration >0.5 log10 at week 12 was achieved in 27 (42.8%), in the TG group (n=45) — only in 5 (11.1%) (OR=6.0, 95% CI 1.96–21.74, P<0.001). SVR was documented in 24 (38.1%) and 7 (15.6%), respectively (OR=3.34, 95% CI 1.20–10.19, P<0.01). At 12 weeks of therapy in the group with TT alleles, a 2 log10 decline in HBV DNA was observed in 58 individuals (92.0%), in the group with TG — in 40 (88.8%) (OR=1.45, 95% CI 0.31–6.73 P=0.575). At week 24: in TT — 63 patients (100.0%) and in TG — 45 patients (100.0%). SVR was achieved in 23 (36.5%) and 8 (17.7%), respectively (OR=2.66, 95% CI 0.99–7.7, P<0.05). Conclusion. The presented study demonstrates that favorable genetic polymorphism IFNL-3 (SNP 12979860 and SNP rs8099917) is one of the most significant baseline positive predictive factors on SVR induction. Keywords HBeAg-negative chronic hepatitis B, peginterferon, IFNL-3 (IL-28B) polymorphism, sustained virological response, HBsAg.

The Impact of IL28B Gene Polymorphisms on Drug Responses

The Impact of IL28B Gene Polymorphisms on Drug Responses

The Impact of IFNλ4 on the Adaptive Immune Response to SARS-CoV-2 Infection.

Genetic polymorphisms at the IFNL4 loci are known to influence the clinical outcome of several different infectious diseases. Best described is the association between the IFNL4 genotype and hepatitis C virus clearance. However, an influence of the IFNL4 genotype on the adaptive immune system was suggested by several studies but never investigated in humans. In this cross-sectional study, we have genotyped 201 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive participants for 3 IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) and stratified them according to the IFNλ4 activity. Based on this stratification, we investigated the association between the IFNL4 genotype and the antibody as well as the CD8+ T cell response in the acute phase of the SARS-CoV-2 infection. We observed no differences in the genotype distribution compared with a Danish reference cohort or the 1,000 Genome Project, and we were not able to link the IFNL4 genotype to changes in either the antibody or CD8+ T cell responses of these patients.

Interferon-λ3 Gene Polymorphic Variants, rs4803217 and rs12980275, Responsiveness to HBV Vaccine and Outcome of HBV and HCV Exposure in Hemodialyzed Patients

Background: In non-uremic populations, rs4803217 in the IFNL3 messenger RNA 3’ untranslated region or rs12980275 downstream of IFNL3 is connected with the spontaneous or therapeutic clearance of HCV and HBV, and rs12980275 is correlated with plasma IFN-λ3 levels. Moreover, rs12980275 is associated with the sustained virological response following antiviral therapy of chronic hepatitis C in hemodialysis patients. Objectives: We investigated IFNL3 polymorphisms, rs4803217 and rs12980275, for association with responsiveness to HBV vaccine and natural consequences of HBV and HCV exposure among hemodialyzed individuals. Methods: The capacity to produce protective anti-HBs titers was recognized if they were ≥ 10 IU/L after vaccination or natural exposure. The IFNL3 rs4803217 (G>T) and rs12980275 (A>G) genetic variants were analyzed using a high-resolution melting curve method in 1,337 hemodialysis subjects. Plasma IFN-λ3 was determined in 188 individuals using ELISA. The Kaplan-Meier method was applied for the analysis of survival probability. Results: The tested polymorphisms did not show associations with the capacity to generate protective anti-HBs titers after HBV vaccination or exposition and self-limitation of HBV exposure. Natural HCV clearance was connected with the IFNL3 rs4803217 GG genotype (OR: 3.036, 95% CI: 1.544 - 5.969, P = 0.001) and haplotypes comprising at least two more frequent alleles but without any variant allele of IFNL3/IFNL4 genetic variants (P < 0.05). Plasma IFN-λ3 levels were not directly influenced by IFNL3 rs4803217 and rs12980275, but differed concerning HBV/HCV serum markers (P = 0.00005) and firmly correlated with anti-HBs titers (r = 0.537, P = 4.15E-16). Both tested polymorphisms were not significantly associated with the survival of hemodialysis patients. Conclusions: Genotyping IFNL3 rs4803217 may be advantageous in the prognosis of natural HCV clearance but does not predict the self-limitation of HBV exposure, responsiveness to HBV vaccine, or hemodialysis patients’ mortality.

Polymorphism rs368234815 of interferon lambda 4 gene and spontaneous clearance of hepatitis C virus in haemodialysis patients: a case-control study

BackgroundIn non-uremic subjects, IFNL4 rs368234815 predicts HCV clearance. We investigated whether rs368234815 is associated with spontaneous HCV clearance in haemodialysis patients and whether it is a stronger predictor of HCV resolution than the IFNL polymorphisms already associated with HCV clearance in dialysis subjects. We also evaluated an association of rs368234815 with patients` survival and alterations in transcription factor binding sites (TFBS) caused by IFNL polymorphisms.MethodsAmong 161 haemodialysis patients with positive anti-HCV antibodies, 68 (42.2%) spontaneously resolved HCV infection, whereas 93 remained HCV RNA positive. Patients were tested for near IFNL3 rs12980275, IFNL3 rs4803217, IFNL4 rs12979860, IFNL4 rs368234815, and near IFNL4 rs8099917. IFNL4 rs368234815 polymorphism (TT/TT, ΔG/TT, ΔG/ΔG) was genotyped by restriction fragment length polymorphism analysis; other IFNL polymorphisms - by high resolution melting curve analysis. We used the Kaplan-Meier method with the log-rank test for survival analysis. In silico analysis included the use of ENCODE TFBS ChIP-seq data, HOCOMOCO, JASPAR CORE, and CIS-BP databases, and FIMO software.ResultsThe probability (OR, 95%CI, P) of spontaneous HCV clearance for rs368234815 TT/TT patients was higher than for the ΔG allele carriers (2.63, 1.38–5.04, 0.003). This probability for other major homozygotes varied between 2.80, 1.45–5.43, 0.002 for rs12980275 and 2.44, 1.27–4.69, 0.007 for rs12979860. In the additive model, rs368234815 TT/TT was the strongest predictor of HCV clearance (6.38, 1.69–24.2, 0.003). Survival analysis suggested an association of the ΔG allele with mortality due to neoplasms (log-rank P = 0.005). The rs368234815 ∆G allele caused TFBS removal for PLAGL1.ConclusionsIn haemodialysis patients, the association of rs368234815 with the spontaneous HCV clearance is better than that documented for other IFNL3/IFNL4 polymorphisms only in the additive mode of inheritance. However, identifying the homozygosity in the variant ∆G allele of rs368234815 means a more potent prediction of persistent HCV infection in haemodialysis subjects that we observe in the case of the variant homozygosity of other tested IFNL3/IFNL4 polymorphisms. Removal of PLAGL1 TFBS in subjects harbouring the rs368234815 ∆G allele may contribute to cancer susceptibility. The association of rs368234815 with cancer-related mortality needs further studies in HCV-exposed subjects.

Interferon lambda 4 gene polymorphisms as a predicting tool of response to hepatitis C virus genotype 4 patients treated with Sofosbuvir and Ribavirin.

The relation between interferon lambda 4 gene (IFNL4) and direct acting antiviral (DAA) regimens in hepatitis C virus (HCV) infected patients is not clear. So, a single nucleotide polymorphisms (SNP) of IFNL4 gene genotypes and its relationship with Sofosbuvir (SOF) and Ribavirin (RBV) treatment response is under consideration. This study aims to investigate the relation between IFNL4 polymorphisms and clearance of HCV genotype 4 for HCV patients. Hence, the appropriate drug can be chosen for each patient. SNP genotyping assay for IFNL4 which formerly known as IL28B (rs368234815) was examined for genomic DNA. The DNA was extracted from whole blood of one hundred patients who documented to have infection with chronic HCV genotype 4 (positive PCR) and treated with SOF and RBV. Patients were diagnosed, previously, as HCV genotype 4 and classified according to drug response into two groups (responders, non-responders). All samples were compared with 50 of non-infected (negative PCR) people (control group). The TT/TT homozygous represents 48% of patients and 66% of non-infected people while the homozygous ∆G/∆G is 21% and 12%, respectively. There is significance to IFNL4 genotypes for the treatment response with the probability value p<0.001. The percentages of the appearance of genotypes TT/TT, TT/∆G and ∆G/∆G for responders were 60%, 28% and 12%, respectively. There is no significance for gender, age, ALT and PLC to treatment response to SOF and RBV, while INR has.

Association of donor IFNL4 genotype and non-relapse mortality after unrelated donor myeloablative haematopoietic stem-cell transplantation for acute leukaemia: a retrospective cohort study

The interferon lambda 4 gene (IFNL4) regulates immune responses by controlling the production of IFNλ4, a type III interferon. We hypothesised that IFNλ4 could play a role in infection clearance or alloreactivity in patients with acute leukaemia who received a myeloablative 10/10 HLA-matched haematopoietic stem-cell transplantation (HSCT). Therefore, we aimed to assess the association between recipient and donor IFNL4 genotype with post-HSCT survival outcomes in patients with acute leukaemia. We did a two-stage retrospective cohort study using the Center for International Blood and Marrow Transplant Research (CIBMTR) repository and database, in which nearly all patients underwent the procedure in the USA. We included patients with acute myeloid leukaemia or acute lymphocytic leukaemia, who received a HSCT at any age from an unrelated 10/10 HLA-matched donor, with a myeloablative conditioning regimen, between Jan 1, 2000, and Dec 31, 2008, and had a pre-HSCT recipient or donor blood sample available. The discovery dataset included patients from an existing National Cancer Institute (NCI) cohort of the CIBMTR database, in which donor and recipient IFNL4 polymorphisms (rs368234815, rs12979860, and rs117648444) were genotyped with TaqMan assays. According to their genotype, donors and recipients were categorised into IFNL4-positive, if they had at least one copy of the allele that supports the production of IFNλ4, or IFNL4-null for the analyses. The findings were independently validated with patients from the DISCOVeRY-BMT cohort (validation dataset) with existing Illumina array genotype data. We also did a combined analysis using data from patients included in both the NCI and DISCOVeRY-BMT cohorts. We assessed 404 patients (who had a HSCT from Jan 9, 2004, to Dec 26, 2008) in the discovery dataset and 1245 patients in the validation dataset (HSCT Jan 7, 2000, to Dec 26, 2008). The combined analysis included 1593 overlapping participants in both cohorts. Donor, but not recipient IFNL4-positive genotype was associated with increased risk of non-relapse mortality (HR 1·60, 95% CI 1·23-2·10; p=0·0005 in the discovery dataset; 1·22, 1·05-1·40; p=0·0072 in the validation dataset; and 1·27, 1·12-1·45; p=0·0001 in the combined dataset). Associations with post-HSCT overall survival were as follows: HR 1·24, 95% CI 1·02-1·51; p=0·034 in the discovery dataset; 1·10, 0·98-1·20; p=0·10 in the validation dataset; and 1·11, 1·02-1·22; p=0·018 in the combined dataset. Prioritising HSCT donors with the IFNL4-null genotype might decrease non-relapse mortality and improve overall survival without substantially limiting the donor pool. If these findings are validated, IFNL4 genotype could be added to the donor selection algorithm. The National Cancer Institute Intramural Research Program. For full funding list see Acknowledgments.

Lack of Association between IFNL3 Polymorphism and Human Papillomavirus Infection and Their Progression in HIV-Infected Women Receiving Antiretroviral Treatment

Background: It has been reported that interferon-λ3 (IFNL3)might influence the pathogenesis and clearance of human papillomavirus (HPV) infection. The impact of IFNL3 single-nucleotide polymorphism (SNP) on HPV infection is currently unknown. The aim of this study was to investigate the association between variants in the IFNL3 region and HPV infection in women with human immunodeficiency virus (HIV) infection. Methods: A total of 236 HIV patients, including 65 HPV-negative and 171 HPV DNA-positive women, were enrolled into this study. The IFNL3 rs12979860 polymorphism was genotyped using a predesigned TaqMan SNP genotyping assay. Results: Data showed no significant differences in genotypes or allele frequencies between the HPV DNA-positive and the HPV-negative women (p > 0.05). After dividing the HPV-positive women according to cytology results into patients with abnormal and normal lesions, the genotype and allele distribution of the SNP did not significantly differ between the 2 groups (p > 0.05). Conclusions: Our results showed that the IFNL3 rs12979860 polymorphism is not a major determinant of the susceptibility to HPV infection and their progression to abnormal cervical lesions in women living with HIV.

IFNL3 rs12980275 Polymorphism Predicts Septic Shock-Related Death in Patients Undergoing Major Surgery: A Retrospective Study

Interferon lambda 3 (IFNL3, previously called IL-28B) is a cytokine with effects against viral and bacterial pathogens. We aimed to analyze the IFNL3 rs12980275 SNP in patients who underwent major surgery, in order to establish its relationship with susceptibility to septic shock and septic shock-related death in these patients. We performed a case-control study on 376 patients to establish the association between IFNL3 rs12980275 SNP and the susceptibility to develop septic shock. Besides, we performed a longitudinal study among 172 septic shock patients using survival analysis with one censoring point of 28-days mortality. The IFNL3 rs12980275 polymorphism was genotyped by Agena Bioscience's MassARRAY platform. IFNL3 rs12980275 polymorphism was not associated with higher susceptibility to infection and septic shock development. Regarding survival analysis, the Kaplan–Meier analysis showed that patients with IFNL3 rs12980275 AA genotype had higher survival than patients with GG genotype (p = 0.003). The Cox regression analysis adjusted by the most relevant clinical and epidemiological characteristics showed that the GG genotype (recessive model) and the presence of the G allele (additive model) were associated with higher risk of death [adjusted hazard ratio (aHR) = 2.15, p = 0.034; aHR = 1.50, p = 0.030, respectively]. In conclusion, IFNL3 rs12980275 polymorphism was associated with septic shock-related death in patients who underwent major surgery. The A allele was linked to protection, and the G allele was associated with an increased risk of death. This is a first preliminary study that suggests for the first time a role of IFNL3 polymorphisms in the prognosis of septic shock.

IFNL3 genotype is associated with pulmonary fibrosis in patients with systemic sclerosis

Fibrosis across different organs and tissues is likely to share common pathophysiological mechanisms and pathways. Recently, a polymorphism (rs12979860) near the interferon lambda gene (IFNL3) was shown to be associated with fibrosis in liver across multiple disease etiologies. We determined whether this variant is a risk factor for pulmonary fibrosis (PF) and worsening cutaneous fibrosis in systemic sclerosis (SSc). Caucasian patients with SSc (n = 733) were genotyped to test for association with the presence of PF and worsening of skin fibrosis. Serum IFN-λ3 levels from 200 SSc cases were evaluated. An association of the IFNL3 polymorphism with PF was demonstrated (OR: 1.66 (95% CI: 1.142–2.416, p = 0.008). The IFNL3 variant was not a risk factor for worsening of skin fibrosis. Functionally, IFN-λ3 serum levels were higher among subjects with PF compared to those unaffected (P < 0.0001). In conclusion, IFNL3 serum levels and the genetic variant known to be associated with liver fibrosis are similarly linked to PF, but not to worsening of skin fibrosis in SSc. These data highlight both common fibrosis pathways operating between organs, as well as differential effects within the same disease.

Interferon-Lambda 4 Gene Polymorphisms Predict Treatment Response in Egyptian HCV Genotype 4 Patients Exposed to Radiation

Background: Direct-acting antivirals (DAAs) has seen a significant increase of the count of patients with hepatitis C virus (HCV) clearing their infection. Interferon Lambda Four (IFNL4) polymorphism plays a distinguished role in spontaneous and treatment-output clearance of HCV infection. Aim of this Work: This study aimed to assess IFNL4 polymorphism among hepatitis C Egyptian patients who were exposed to radiation, compared to normal by a polymerase chain reaction with restriction of fragment length polymorphism (PCR-RFLP) technique. Materials and Method: This study included 50 HCV-positive Egyptian patients working in Egyptian Nuclear materials Authority treated with DAAs therapy. According to treatment, they were split into two groups. Group I included 40 patients with sustained viral response (SVR). Group II included 10 patients with no response (nSVR). Fifty healthy people served as controls. Liver function tests, complete blood count, evaluation of viral markers, HCVRNA by PCR, and evaluation for IFNL4 single nucleotide polymorphisms for rs368234815 were performed by PCRRFLP in all patients. Results: Of the 50 patients, 40 (80%) achieved sustained virological response (SVR). Of the 23 patients with rs368234815 TT/TT genotype, 21 (91.3%) achieved SVR, while in 27 patients with non‑ TT/TT genotypes, 19 (70.4%) achieved SVR. The rs368234815 was a powerful predictor of SVR. However, in the present research individuals, the predictive power of this SNP was the same as that of rs12979860 SNP. Conclusion: In Egyptian HCV-positive patients with genotype 4, IFNL4 rs368234815 SNP is an autonomous predictor of SVR to DAAs treatment.

IFNL4 haplotype, linkage disequilibrium and their influence on virological response to hepatitis C virus infection in Indian population.

Type III interferon (IFNs) encoded by IFN lambda (IFNL) genes induce antiviral activity. The IFNL clusters include IFNL1/IL29, IFNL2/IL28A, IFNL3/IL28B and IFNL4 genes. The single nucleotide polymorphisms (SNPs, rs12979860 and rs8099917) associated with virological responses against hepatitis C virus (HCV) infections are recently mapped to IFNL4 gene. The IFNL gene polymorphisms also plays role in immune clearance, inflammation and risk of developing hepatocellular carcinoma. There is significant genetic heterogeneity of IFNL4 polymorphisms among ethnic populations that need to be regionally studied for viral infection, treatment response and relapse. The IFNL4 risk allele, genotype and haplotype frequencies across north Indian cohort were determined among chronic hepatitis C (CHC) cases (n = 141) and healthy controls (n = 111) by allele specific real-time PCR. Odds ratio was calculated for HCV exposure and treatment response using dominant and minor allele/genotype as reference. Non-random associations of these two SNP loci were evaluated by linkage disequilibrium plot. The minor allele (T) frequency of rs12979860C/T is 0.241 and 0.229; and minor allele (G) frequency for SNP rs8099917T/G is 0.174 and 0.171 among CHC cases and healthy control respectively. Coefficient of linkage disequilibrium (D') of these two SNPs is very high (D' = 0.98, r2 > 0.6) in CHC group than in healthy control (D' = 0.76, r2 = 0.39) which indicate that both SNPs are strongly linked in CHC population than healthy control. Favorable association of IFNL4 haplotype (C-T), genotype (CC for rs12979860 and TT for rs8099917) with anti HCV therapy were found significant (p = 0.009, 0.021 and 0.001) for SVR. Favorable genotypes are also found to be predominant across the Indian study population.

Association of HLA-DQ and IFNL4 polymorphisms with susceptibility to hepatitis B virus infection and clearance

Background and aim. Leukocyte antigen DQ (HLA-DQ) and interferon-λ4 (IFNL4) gene polymorphisms were associated with susceptibility to chronic hepatitis B and C virus infection. This study further confirmed that variants of these genes were associated with susceptibility and spontaneous clearance of HBV infection in a Chinese population.Material and methods. A total of 1,069 subjects were recruited and divided into three groups i.e. 397 with CLD (HBV-related chronic liver disease), 434 with SC (spontaneous clearance), and 238 HC (healthy controls). HLA-DQrs9275319 and IFNL4rs368234815, rs12971396, rs12979860, and rs8099917SNPs were genotyped using the Sequenom MassARRAY MALDI-TOF system.Results. HLA-DQ rs9275319 showed a significant association with HBV infection (allele model, OR, 0.514; 95% CI, 0.359-0.738, adjusted p = 0.0003) and with natural clearance (allele model, OR, 1.659; 95% CI, 1.197-2.300, adjusted. However, there was no association between IFNL4 polymorphism and HBV susceptibility or natural clearance (all p > 0.05). The multjfactor dimensionality reduction (MDR) test with permutation correction showed that a three-way interaction between IFNL4 and HLA-DQ SNPs was identified for HBV susceptibility (permutation p = 0.009 for the best factor model) and clearance (permutation p = 0.014 for the best factor model).Conclusions. The data from the current study provided additional evidence for an SNP-SNP interaction between HLA-DQ and IFNL4 in regulation to HBV infection and natural clearance.

The impact of IFNL3 genotype on interferon treatment outcome in patients chronically infected with hepatitis B virus: A meta-analysis

BackgroundPolymorphisms near the interferon lambda 3 (IFNL3, also known as IL28B) have been proposed to be associated with interferon (IFN)–induced hepatitis C virus (HCV) clearance, but the impact of IFNL3 variations on the result of IFN-based therapy in chronic hepatitis B (CHB) infection is still poor understood. MethodsThe purpose of this study was to evaluate the relationship between the IFNL3 polymorphisms and the effectiveness of IFN therapy in patients infected with CHB by means of meta-analysis. PubMed and Embase were utilized to identify relevant studies. Odds ratio (OR) and 95% confidence interval (CI) were analysed together to assess the strength of the association. Subgroup analysis was mainly performed according to HBeAg. ResultsTwelve studies of 1645 CHB patients met the inclusion criteria and were selected in our meta-analysis. One polymorphism, rs12979860, near to the IFNL3 gene had significant association with the response of CHB patients to IFN-based therapy (OR = 2.35, 95% CI: 1.61–3.42 in allelic model). Another polymorphism, rs8099917, had a similar result (OR = 1.57, 95% CI: 1.03–2.40 in dominant model; and OR = 1.88, 95% CI: 1.21–2.90 in allelic model). When stratified by HBeAg, the antiviral outcome was markedly influenced by both two SNPs in HBeAg positive group (for rs12979860, OR = 1.90, 95% CI: 1.31–2.76 and OR = 2.07, 95% CI: 1.26–3.41 in dominant and allelic models respectively; for rs8099917, OR = 1.67, 95% CI: 1.04–2.67 in dominant model and OR = 1.77, 95% CI: 1.10–2.85 in allelic model). ConclusionWe concluded that two polymorphisms (rs12979860 and rs8099917) of IFNL3 may play a crucial role in the IFN-based treatment of CHB, especially in HBeAg positive group.

Association of serum interferon-λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents.

Although the efficacy of hepatitis C virus (HCV) treatment is improved dramatically by direct-acting antiviral agents (DAAs), the assessment of hepatocellular carcinoma (HCC) remains important. Interferon lambda 3 (IFN-λ3) is associated with liver fibrosis and inflammation in chronic hepatitis C (CHC) patients, but its impact on carcinogenesis remains controversial and little is known about its effects after viral clearance. To determine the contribution of IFN-λ3 to hepatocarcinogenesis after HCV clearance, we analyzed IFNL3 genotypes and serial serum IFN-λ3 levels in CHC patients who achieved sustained virologic responses (SVR). This study comprised 201 CHC patients treated with DAAs. Serum samples were collected sequentially and IFN-λ3 levels were quantified by chemiluminescence enzyme immunoassay. The IFNL3 polymorphism (rs8099917) was genotyped in 195 patients. One hundred and twenty-five patients were rs8099917 T/T and 70 were non-T/T. Serum IFN-λ3 levels did not differ significantly with IFNL3 genotype, dropped markedly by 1week and remained low up to 24weeks after the end of treatment. Interferon-λ3 levels were significantly higher after viral clearance in patients who developed HCC and were associated with a higher potential for hepatocarcinogenesis, such as a higher frequency of non-hypervascular hypointensive nodules (P = 0.046), higher stages of liver fibrosis (P < 0.001), and higher post-treatment levels of Wisteria floribunda agglutinin positive Mac-2 binding protein (P < 0.001) and alanine aminotransferase (P < 0.001). Serum IFN-λ3 levels after HCV clearance are associated with the potential for HCC development. Interferon-λ3 could be helpful for elucidating the relationships among immunologic status, liver fibrosis, liver inflammation, and hepatocarcinogenesis, after achieving SVR.

No association between IFNL3 (IL28B) genotype and response to peginterferon alfa-2a in HBeAg-positive or -negative chronic hepatitis B.

Background & aimsIt has yet to be firmly established whether host IFNL3 (IL28B) genotype influences interferon responsiveness in patients with chronic hepatitis B. We investigated associations between single-nucleotide polymorphisms (SNPs) in the IFNL3 region and response to peginterferon alfa-2a in 701 patients enrolled in three large, randomized, international studies.MethodsResponses were defined as hepatitis B surface antigen (HBsAg) loss and/or hepatitis B e antigen (HBeAg) seroconversion plus hepatitis B virus (HBV) DNA <2000 IU/ml in HBeAg-positive patients, and HBsAg loss and/or HBV DNA <2000 IU/ml in HBeAg-negative patients (24 weeks after end of treatment). Associations between treatment response and the number of copies of the poor-response allele at three SNPs (rs8099917, rs12980275, rs12979860) were explored with logistic regression models in Asian and white patients.ResultsThe HBeAg-positive and -negative populations comprised 465 (92% Asian, 50% HBV genotype C) and 236 (79% Asian, 41% HBV genotype C) patients, respectively, and had respective response rates of 26% and 47%. The IFNL3 genotype was strongly associated with ethnicity. There was no association between IFNL3 genotype and treatment response in HBeAg-positive or -negative patients. Independent predictors of treatment response were: sex, HBV DNA level and alanine aminotransferase level in HBeAg-positive Asian patients; age in HBeAg-negative Asian patients; and HBV DNA in HBeAg-negative white patients.ConclusionsThis is the largest analysis to date of associations between IFNL3 genotype and peginterferon response in patients with chronic hepatitis B. The data suggest that IFNL3 polymorphism is not a major determinant of the response to peginterferon alfa-2a in either HBeAg-positive or HBeAg-negative patients.

Interferon‑λ4 gene polymorphisms, circulating interferon λ3, and clinical variables in hemodialysis patients exposed to hepatitis E virus.

Introduction Factors associated with hepatitis E virus (HEV) infection are rarely recognized in patients on renal replacement therapy (RRT), and the results of studies are inconsistent. Objectives We aimed to search for determinants of HEV seroprevalence among polymorphisms of the interferon‑λ4 gene (IFNL4) associated with seroclearance of hepatotropic viruses (IFNL4 rs12979860, rs8099917 near IFNL4), circulating interferon λ3 (IFN‑λ3), and clinical variables of patients treated with hemodialysis (HD) in a HEV‑endemic region. Patients and methods The study was carried out in 90 HD patients. HEV open reading frame 2 antigen (HEV Ag), immunoglobulin M and G antibodies to HEV (anti‑HEV IgM and anti‑HEV IgG, respectively) and IFN‑λ3 were tested, and IFNL4 polymorphic variants (rs8099917, rs12979860) were genotyped. Survival analysis was conducted concerning anti‑HEV IgG positivity. Results In the study group, there were 37.8% anti‑HEV IgG‑positive subjects. None was HEV Ag or anti‑HEV IgM positive. HD modalities utilizing high‑flux dialyzers (adjusted odds ratio [OR], 3.586; 95% confidence interval [CI], 1.142-11.263; P = 0.03) as well as major homozygosity in rs8099917 (adjusted OR, 4.933; 95% CI, 1.516-16.054; P = 0.008) and rs12979860 (adjusted OR, 3.537; 95% CI, 1.136-11.014, P = 0.03), but not circulating IFN‑λ3 levels, were positive determinants of anti‑HEV IgG positivity. Liver enzyme activities and C‑reactive protein levels tested as response variables to HEV exposure, as well as survival probability, were not different between patients stratified by anti‑HEV IgG positivity. Conclusions Among HD patients, IFNL4 polymorphisms and treatment with high‑flux HD are explanatory variables for isolated anti‑HEV IgG positivity indicating spontaneous HEV resolution.

Modulation of Immune Responses toHerpes Simplex Virus Type1 by IFNL3 and IRF7 Polymorphisms: AStudy inAlzheimer's Disease.

Herpes simplex virus type 1 (HSV-1) has long been suspected to play a role in Alzheimer's disease (AD), the most common form of dementia. IFN-lambda (IFN-λ) is one of the key cytokine in innate antiviral defenses and, in particular, has an appreciable antiviral activity against HSV-1 infection. IFN-λ expression is regulated by the interaction between two different proteins: Mediator Complex 23 (MED23) and Interferon-Responsive Transcription Factor 7 (IRF7); single nucleotide polymorphisms (SNPs) in these genes as well as in IFNL3 were shown to be differently distributed in AD patients. In this study, allelic discrimination analysis for IFNL3 rs12979860, MED23 rs3756784, and IRF7 rs6598008, as well as IFN-λ serum concentration and anti-HSV-1 antibody (Ab) titers were performed in 79 AD patients, 57 mild cognitive impairment (MCI) individuals, and 81 healthy controls (HC) who were HSV-1-seropositive. Results showed that INF-λ serum concentration was increased in AD and MCI carrying the IFNL3 T allele compared to HC (AD versus HC: p = 0.014; MCI versus HC: p = 0.029), with the highest anti-HSV-1 Ab titers seen in AD patients carrying the IFNL3 CC genotype (p = 0.012 versus HC). Notably, anti-HSV-1 Ab titers were higher in AD and MCI individuals carrying the IRF7 AA genotype compared to HC (p = 0.018 for both). MED23 polymorphisms did not show any statistical association either with serum IFN-λ or with anti-HSV-1 Ab. Data herein suggest that the IFNL3 rs12979860 and IRF7 rs6598008 polymorphisms modulate immune responses against HSV-1 via their effect on the IFN-λ pathway. These results help to clarify the possible role of HSV-1 infection in AD pathogenesis.